An Aptamer That Rapidly Internalizes into Cancer Cells Utilizes the Transferrin Receptor Pathway

Author:

Song Xirui12,Yu Haixiang1,Sullenger Cynthia3,Gray Bethany Powell14ORCID,Yan Amy1,Kelly Linsley1ORCID,Sullenger Bruce12ORCID

Affiliation:

1. Department of Surgery, Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USA

2. Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA

3. Department of Biology, Duke University, Durham, NC 27710, USA

4. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

Abstract

Strategies to direct drugs specifically to cancer cells have been increasingly explored, and significant progress has been made toward such targeted therapy. For example, drugs have been conjugated into tumor-targeting antibodies to enable delivery directly to tumor cells. Aptamers are an attractive class of molecules for this type of drug targeting as they are high-affinity/high-specificity ligands, relatively small in size, GMP manufacturable at a large-scale, amenable to chemical conjugation, and not immunogenic. Previous work from our group revealed that an aptamer selected to internalize into human prostate cancer cells, called E3, can also target a broad range of human cancers but not normal control cells. Moreover, this E3 aptamer can deliver highly cytotoxic drugs to cancer cells as Aptamer-highly Toxic Drug Conjugates (ApTDCs) and inhibit tumor growth in vivo. Here, we evaluate its targeting mechanism and report that E3 selectively internalizes into cancer cells utilizing a pathway that involves transferrin receptor 1 (TfR 1). E3 binds to recombinant human TfR 1 with high affinity and competes with transferrin (Tf) for binding to TfR1. In addition, knockdown or knockin of human TfR1 results in a decrease or increase in E3 cell binding. Here, we reported a molecular model of E3 binding to the transferrin receptor that summarizes our findings.

Funder

NIH

Publisher

MDPI AG

Subject

Cancer Research,Oncology

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